Method of producing gamma-keto acids



United States Patent 3,412,116 METHOD OF PRODUCING y-KETO ACIDS Heinz Reinheckel, Berlin, Klaus Haage, Berlin-Pankow,

and Rita Gensike, Berlin-Baumschulenweg, Germany,

assignors to Deutsche Akademie der Wissenschaften zu Berlin, Berlin-Adlershof, Germany No Drawing. Filed Nov. 1, 1965, Ser. No. 505,966

5 Claims. (Cl. 260413) ABSTRACT OF THE DISCLOSURE 'y-Keto acids are prepared by reacting dicarboxylic dihalides with organic aluminum chlorides or bromides in solutions in partially halogenated hydrocarbons at temperatures of +20 to 50 C. and hydrolyzing the product of this reaction.

The present invention relates to a method of producing 'y-keto acids, and more particularly to the production of such v-keto acids as 'y-keto-carboxylic acids by means of aluminum organic compounds such as aluminum alkyls.

'y-Keto acids are useful in the fat industry as raw material for the production of taste-forming 'y-hydroxy fatty acid-lactones.

These compounds are also valuable as surface active agents and find particular application as starting products in the wetting agent and washing agent industries.

'y-Keto acids of various structures are also necessary in the plastics industry.

It is known that 'y-keto acids can be obtained from acetyl succinic acid-diester, maleic acid-diester of ethyl aceto acetate by condensation reactions with monocarboxylic acid chlorides or succinic acid esterchloride and by subsequent decomposition of the obtained condensation product.

Methods are also known wherein preformed 'yfunctional monocarboxylic acid derivatives are converted into 'y-keto acids. Thus, for example, v-lactones of hydroxy carboxylic acids can easily be oxidized by means of bromine to the corresponding 'y-keto acids, and 'y-keto acids can also be produced from 'y-nitrocarboxylic acids by the action of dilute sulfuric acid.

Another known method comprises the production of 'y-ketO acid nitriles by hydrogen cyanide addition of compounds of the type of alkylene-(1)-one-(3). Furthermore, secondary and tertiary furfuryl carbinols can be split by alcoholic hydrochloric acid to the corresponding 'y-keto acid esters.

In many methods the 'y-keto acids are formed in addition to other reaction products. Thus, for example, upon the oxidation of ammonium salts of aliphatic monocarboxylic acids there are obtained the corresponding 'y-keto acids and the 6-keto acids. By the decomposition of diazoketones =with diazo acetic ester in the presence of copper oxide, considerable amounts of 'y-ketO acid esters are obtained among other reaction products.

The use of metal alkyl compounds to aid in the production of 'y-keto acids is only known for a few methods.

Thus, N-methyl-succinimide can be converted with alkyl magnesium halides into precursors of 'y-keto acids l-methyl-2-alkyl-pyrrolone-(5) Succinic acid ester chloride can be reacted with butylzinc iodide or cadmium-dialykyls to v-keto acid esters.

Finally, 'y-keto acid esters are obtained in very small yield by the reaction of succinic acid esterchloride with alkylaluminum chlorides of phenylaluminum chlorides and O-acylated aromatic carboxylic acid with alkylmagnesium halides.

All of the known methods of producing v-keto acids or their esters exhibit some shortcomings.

In general, these methods require many reaction steps With partial isolation at least of the intermediate products, whereby the yields are reduced and the method costs increased.

Moreover, many of the methods cannot be used for the production of all desired chain lengths of aliphatic or substituted 'y-keto acids.

In all of the methods with good yields, in which the starting product already has the 'y-function pre-formed, as well as for methods in which alkylmagnesium halides or cadmium alkyl compounds are used, require troublesome reactions or the purification of the starting product. An additional disadvantage consists in the instability of magnesium alkyl compounds and cadmium alkyl compounds which requires their storage and use in solvents.

The method of producing 'y-keto acid esters from succinic acid ester chloride with alkylaluminum chlorides or phenylaluminum chlorides require the production of pure succinic acid esterchlorides through several reaction steps and leads to the production of entirely unsatisfactory yields of 'y-keto acid esters. Furthenmore, these esters must be saponified to obtain the free acids.

It is accordingly a primary object of the present invention to provide for the production of 'y-keto acids in a single stage process in high yield and with a minimum of undesired side products.

It is another object of the present invention to provide for a simple method of producing 'y-keto acids in high yields by the use of aluminum organic compounds such as aluminum alkyls.

It is still a further object of the present invention to provide for high yield, reproducible production of 'y-keto acids directly without the need for subsequent saponification in order to obtain the free acids.

Other objects and advantages of the present invention will be apparent from a further reading of the specifica tion and of the appended claims.

With the above and other objects in view, the present invention mainly comprises the preparation of a y-keto acid of the formula:

wherein R is an aliphatic, araliphatic, cycloaliphatic or aromatic radical and wherein U, W, Y and Z are each independently selected from the group consisting of hydrogen, aliphatic radicals, arylaliphatic radicals, cyclo aliphatic radicals and aromatic radicals, and U, W, Y and Z together with the carbon atoms to which the same are attached are selected from the group consisting of homocyclic and heterocyclic ring systems, by reacting dicarboxylic dihalides of the formula:

ll YZ Among the suitable solvents are partially halogenated hydrocarbons, particularly methylene chloride.

The reaction temperature for the reaction of the present invention is generally between +20 C. and 50" C., and is preferably between -35 C. and 25 C.

The mol ratio of dicarboxylic acid dihalide to aluminum organic compound should preferably be approximately 11, or should not considerably deviate therefrom, whereby it has the same meaning as in Formula 111 above.

The reaction proceeds under these conditions entirely to the stage of the monoalkylated product, that is to the 'y-keto acid halide. It proceeds better and in higher yield when rz:1, that is when a monoalkylaluminum dihalide is used.

Based on the known aluminum organic syntheses, the aluminum trialkyl compounds are more easily obtainable in industrial practice. However, it is not necessary to produce alkylaluminum dihalides from aluminum trialkyls, since according to the present invention it has been found that if an aluminum trialkyl compound is added dropwise to a mixture of a water-free aluminum halide and a dicarboxylic acid dihalide the action is completely that of an alkylaluminum dihalide if the molar ratio of dicarboxylic acid dihalide to aluminum halide to aluminum trialkyl is 3:2: 1.

However, a somewhat smaller or greater amount of aluminum halide can be used if the ratio is maintained between the values of about 3:0.511 and 3:6:1. These limiting values influence the time of reaction and the yield, and values outside of the range have an undesirable effect thereon.

The corresponding 'y-keto acid halides are in the form of cyclic molecules. They are preferably hydrolyzed by introducing the same into cooled dilute sulfuric acid of a concentration of between about 5 and 30%. The temperature during the first stage of the hydrolysis, that is during the introduction of the reaction product in the hydrolysis medium, should be maintained below C., and preferably between about 30 C. and C. This can be achieved by careful introduction of the cold reac tion product into the already precooled hydrolysis medium under vigorous stirring.

Thereafter, the hydrolysis mixture can be maintained for a long period of time at room temperature in order to complete the hydrolysis.

The 'y-keto acids can be separated from the aqueous phase in normal manner, particularly by the use of solvents. If the hydrolysis proceeds very slowly, the still not completely hydrolyzed organic phase can be converted into the 'y-keto acid by further stirring with pure water or with an aqueous alkaline solution (5-20%).

The method of the present invention provides a tech nically suitable method of producing 'y-keto acids in good yield, that is in yields of about 60-90% of the theoretical. The aluminum organic compounds such as the aluminum alkyls can be completely utilized for the reaction, e.g. the alkylation.

The dicarboxylic acid dihalides which are used as starting material for the method of the invention, of which the most important representatives are succinic acid dichloride and phthalic acid dichloride, can be much more easily obtained in pure form than the dicarboxylic acid ester halides which are used for other methods.

The following examples are given to more fully illustrate the present invention. The scope of the invention is not, however, meant to be limited to the specific details of the examples.

Example 1.Production of 'y-ketocaproic acid 49.5 g. of aluminumethyl sesquichloride (0.4 mol) dissolved in 70 g. of methylene chloride are added slowly under vigorous stirring at 30 C. to 25" C. to 77.5 g. of succinic acid dichloride (0.5 mol) in 250 g. of methylene chloride so that the heat of reaction is carried off by cooling from the outside. After bringing the reac tion components together, the above mentioned temperature is maintained for an additional 3 hours while stirring.

Up to the beginning of the hydrolysis the reaction must be carried out under the strict exclusion of air and moisture, and this is accomplished by the passing of a dry inert gas (pure nitrogen) over the reaction mixture.

The reaction product is, for hydrolysis purposes, added under stirring to 200 g. of approximately 15% sulfuric acid at a temperature of 20 C., whereby as a result of careful cooling care is taken that the temperature of the hydrolysis mixture during the introduction does not increase to above 10 C. The mixture is then permitted to warm to room temperature and the organic phase (reaction product plus methylene chloride) is subsequently separated from the aqueous phase after the addition of 100 g. of ether. The aqueous phase is extracted with ether. The total yield is 59 g. of 'yketo caproic acid (equivalent to 90.8% of the theoretical): B.P. =l45- 147 C.; M.P.=35-37 C.

Example 2.Production of a,}8-dimethyl-'y-phenyl-yketobutyric acid 97 g. of phenylaluminum sesquibromide (0.37 mol) dissolved in 100 g. of methylene chloride are slowly added under vigorous stirring at a temperature of 20 C. to 15 C. to 91.5 g. of a,a'-dimethyl succinic acid dichloride (0.5 mol) in 250 g. of methylene chloride. The working up of the reaction product proceeds as in Example 1, however in order to complete the hydrolysis of the formed ketocarboxylic acid chloride the separated organic phase is vigorously stirred with pure water for an additional 3 hours. The aqueous phase is then again extracted with ether. The yield is 87 g. of a,B-dimethyl- 'y-phenyl-y-ketobutyric acid, which is equivalent to 84.2% of the theoretical.

Example 3.--Production of y-kClOCElpIiC acid 93 g. of succinic acid dichloride (0.6 mol) are added to 53.5 g. of aluminum chloride (water-free) (0.4 mol) in 400 g. of methylene chloride. After a solution has been formed, it is cooled to 25" C. and the addition of 56.5 g. of aluminum tri-n-hexyl (0.2 mol) is started. The further 'working up of the reaction product proceeds as in Example 1, however subsequently in order to complete the hydrolysis the organic phase is further stirred with 250 g. of 10% sodium hydroxide solution. The resulting 'y-ketocapric acid is obtained after neutralization with hydrochloric acid. The yield is 88.5 g. of 'y-keto capric acid which is equivalent to 78.5% of the theoretical. The melting point is 66-67 C.

Example 4.Production of a mixture of aliphatic 'y-keto fatty acids from the product of ethylene addition onto aluminum trialkyl 233 g. of succinic acid dichloride (1.5 mol) are added to 134 g. of water-free aluminum chloride (1.0 mol) in 750 g. of methylene chloride and to this mixture is added slowly under stirring at -15 C., 280 g. of a product of ethylene addition on aluminum triethyl with an average chain length of C which product contains, besides hydrocarbons, by weight of pure aluminum alkyl compound. The addition is dropwise. The further working up of the reaction product proceeds in analogy to Example 3. The yield is 254 g. (:to 73.3% of the theoretical) of a mixture of -keto fatty acids (C .H. O wherein n is an integer greater than 2 and statistically averages 7. The reaction product is subjected to pressure hydrogenation with Raney-nickel at 100 atmospheres pressure at 165 C. to provide a yield of a mixture of 'y-hydroxy fatty acid lactones.

Example 5.Production of e-phenyl-y-ketocaproic acid 95 g. of di-fi-phenylethylaluminum bromide in g. of bromobenzene (0.3 mol) are added under vigorous stirring at 30 C. to -25 C. to 122 g. of succinic acid dibromide (0.5 mol) in 300 g. of brornobenzene. The further working up proceeds as described in Example 1 with the addition of the 3 hour mixing of the onganic phase with pure water as described in Example 2. The aqueous phase is again extracted with ether. The yield is 71 g. of e-phenyl- -ketocaproic acid which is equivalent to 69% of the theoretical.

Example 6.Production of propiophenone-O-carboxylic acid 25 g. of ethylaluminum sesquichloride (0.2 mol) dissolved in 75 g. of methylene chloride are slowly added under stirring at 35 C. to 30 C. to 50 g. of symmetrical O-p'hthalyl chloride (0.25 mol) in 200 g. of methylene chloride. After bringing together of the reaction components, the reaction solution which is slowly turning reddish brown is maintained for an additional 2 hours under stirring at 30 C. and then hydrolyzed at C. by introduction into 200 g. of sulfuric acid.

The organic phase is separated and stirred twice at room temperature with 200 g. of potassium hydroxide to complete the hydrolysis of the formed keto acid chloride. The alkaline solution is neutralized with cold hydrochloric acid and the formed keto acid is extracted with ether. The yield is 37 1g. of propiophenone- O-carboxylic acid, which is equivalent to 83% of the theoretical. The melting point is 93 C.

Example 7.--Production of 'y-ketolauric acid 23 g. of octylaluminum dichloride (0.11 mol) are slowly added under vigorous stirring at -30 C. to C. to 15.5 g. of succinic acid dichloride (0.10 mol) in 50 g. of methylene chloride. The reaction mixture is then maintained for 2 hours at 25 C. to 20 C. and subsequently hydrolyzed as in Example 1 and further worked up, with the addition of the further stirring of the organic phase with pure water as described in Example 2. The yield is 18 g. of 'y-ketolauric acid (=84.0% of the theoretical), melting at 7677 C.

Example 8.Production of benzyl- -ketocapric acid 18 g. of hexylaluminum dichloride (0.10 mol) are very slowly added under vigorous stirring at 25 C. to 20 C. to 24.5 g. of benzyl succinic acid dichloride (0.10 mol) in 80 g. of chlorobenzene. The mixture is maintained for 2 hours at 20 C., then hydrolyzed as in Example 1 and subsequently the organic phase is stirred with dilute sodium hydroxide solution and worked up as described in Example 3.

The yield is 17 g. of crude benzyl-'y-ketocaproic acid (=61.5 of the theoretical).

Example 9.Production of a mixture of aand /3phenyl--y-ketocaproic acid 11.5 g. of diethylaluminum bromide (0.07 mol) are slowly added under vigorous stirring at 25 C. to -20 C., to 23.1 g. of phenyl succinic acid dichloride (0.10 mol) in 80 g. of methylene chloride. The mixture is maintained for 3 hours at 25 C. and subsequently hydrolyzed as described in Example 1 and further worked up analogously to Example 3.

The yield is 13 g. of a mixture of aand fl-phenyl-yketocaproic acid (equivalent to 63.0% of the theoretical).

While the invention has been described in particular with respect to the production of certain -y-keto acids in accordance with the method of the present invention, it is apparent that these examples are illustrative only, and it is further apparent that modifications and variations of the method described can be made without departing from the spirit or scope of the invention. Accordingly, such variations and modifications are meant to be comprehended within the meaning and scope of equivalents of the appended claims.

6 What is claimed is: 1. The method which comprises the preparation of keto acids of the formula:

OOOH

wherein R is ethyl, hexyl or octyl radical or a mixture of ethyl radical and ethylene addition product radical, the ethylene addition product radical having an average chain length of C and the mixture of radicals having an average chain length of C phenyl or phenylethyl radical, and wherein U, W, Y and Z are each independently selected from the group consisting of hydrogen, methyl, phenyl and benzyl radicals or wherein U, W, Y, and Z together with the carbon atoms to which the same are attached constitute which comprises reacting dicarboxylic dihalides of the formula:

wherein U, W, Y and Z have the same definitions as above and X is chlorine or bromine with organic aluminum compounds of the formula:

wherein R and X have the same meaning as above and n is between 1 and 3 in the presence of partially halogenated hydrocarbons as solvent at temperatures ranging from +20 to -50 C. and hydrolyzing the product of this reaction.

2. The method according to claim 1 in which aluminum trihalide is present in the reaction and the ratio of said dicarboxylic acid dihalide to said aluminum trihalide to said organic aluminum compound is between about 3:611 and 310.5: 1.

3. The method according to claim 1 wherein the reaction product of the reaction of said dicarboxylic acid dihalide and said aluminum organic compound is subjected to acid hydrolysis by means of dilute sulfuric acid of 5 to 30% at a temperature between about 30 C. and 0 C.

4. The method according to claim 3 wherein the reaction product of the hydrolysis is stirred with pure water to complete the hydrolysis.

5. The method according to claim 3 wherein the reaction product of the hydrolysis is stirred with aqueous alkaline solution to complete the hydrolysis.

References Cited UNITED STATES PATENTS Re. 25,797 6/1965 Mirviss et al 260-413 3,217,020 11/1965 Ziegler et al. 260413 OTHER REFERENCES Bertsch and Reinheckel: Fette, Seifen, Anstrichmittel 64, 881-6 (1962).

Reinheckel: Angew. Chem. 76 (14), 64647 (1964).

Pasynkiewicz et al.: CA. 59: 864od, abstract of: Roczniki Chem. 37, 293-300 (1963), ibid. 31-43.

Pasynkiewicz et al.: CA. 60: 1442oc, abstract of Roczniki Chem. 38, (1) 67-78 (1964).

Morrison and Boyd: Organic Chemistry, Allyn and Bacon, Inc., Boston, Mass., 1961, pp. 472474, QD 251 M72.

NICHOLAS S. RIZZO, Primary Examiner.

R. V. RUSH, Assistant Examiner. 

